This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Apoptosis is a fundamental process in metazoan development. It is a central component of countless events during animal development that serve to sculpt and shape structures, eliminate obsolete cells and tissues, and closely control cell number. Beyond development, apoptosis plays a critical role throughout the life of an organism for the maintenance of tissue architecture and homeostasis. Most critically, it serves as a means for the selective removal of aberrant cells that could otherwise become a liability to a multi-cellular organism. Defects in apoptosis are associated with a number of debilitating conditions including cancer, autoimmune disorders, and neurodegenerative diseases. An in-depth understanding of the mechanisms and regulation of apoptosis is central to the development of new, more effective therapies for these conditions. This proposal explores the regulation of apoptosis in the context of Drosophila retinal patterning. Specifically, the focus is a new pro-apoptotic gene, morgue, isolated in a genetic screen for mutations that disrupt developmentally regulated apoptosis in Drosophila. Morgue encodes a ubiquitin conjugase related molecule that promotes cell death by disrupting the function of the Drosophila inhibitor of apoptosis protein-1 (DIAP1). Morgue interacts directly with DIAP1 and promotes its degradation, facilitating the progression of downstream events. Recent data suggests that Morgue is an apoptosis-specific molecule subject to extensive post-translational regulation. This is addressed in the current study through genetic, molecular, and biochemical approaches designed to assess the role of known death regulators in Morgue function, and identify new molecules never before implicated in apoptosis.